The invention relates to substantive water-soluble his-quatemary salts of cinnamidoalkylamines. More particularly, the invention relates to novel, cationic, non-hydrolysable, non-irritating UV-absorbing bis-quaternary salts of cinnamidoalkylamines which are substantive to fabric, skin and hair. The invention also relates to a process of manufacture of the said compounds and further to their use in hair, skin and fabric care formulations.
The harmful effects of solar UV-radiation on skin are well known. The UV-B (290-320 nm) portion of solar spectrum is largely responsible for erythema (sunburn) and cancer. [M. M. Rieger, Cosmet. Toiletries, 102 (3), 91, (1987); L. Taylor, Skin Cancer Foundation J., 4, (90) (1986)].
Similarly, photodegradative effect of UV-radiation on human hair is well documented. Continuous exposure to sunrays makes human hair color and makes human hair rough, brittle and difficult to comb. UV rays are reported to damage the proteins of cuticles. Prolonged irradiation results in diminished tensile strength due to breaking of disulphide bonds in keratin, [R. Beyak et al, J. Soc. Cosmet. Chem. 22, 667-668 (1971), E. Hoting et al, J. Soc. Cosmet. Chem. 46, 85-99 (1995)].
In addition, UV light is also known to fade garments. [P. C. Screws, Text. Chem. Color, 11, 21 (1987); B. Milligan et al, Polym. Degrad. Stab. 10 (4), 335 (1985)].
A number of UV-absorbing compounds like derivatives of salicylic acid, benzophenones, benzotriazoles, cinnamic acid have been used in personal care products. However, all these molecules suffered from a major disadvantage of lack of substantivity. To make this UV-absorbing moieties more substantive, structural modification have been introduced.
U.S. Pat. No. 5,601,811 (1997) describes substantive UV-absorbing quaternary ammonium compounds containing cinnamidoalkylamine and product compositions for detergents, household cleaners and hair and skin personal care products. However, these products are said to be either water-soluble or water-dispersible. Bis-quaternary compounds of U.S. Pat. No. 4,734,277 (1988) are synthesised from cinnamidoalkylamine and alkylchlorohydrin forming a linker of an alkyl group with a hydroxyl group beta to one of the quaternary nitrogens, thus giving an unsymmetrical bis-quaternary molecule.
The main object of the present invention is therefore to synthesise highly water-soluble molecules containing cinnamido moiety to provide UV absorption and with cationic centre to provide substantivity to skin, hair and fabric.
The inventors have found that symmetrical bifunctional quaternising agents with oxyethylene linkage in the synthesis of UV-absorbing bis-quaterneries boosts hydrophilicity. High water solubility is desirable because these kind of substantive compounds can be formulated in oil-free compositions so that greasy feel of cosmetic preparations based on hydrophobic carrier can be avoided. Due to their substantive nature constant reapplication of the sunscreen preparation is not necessary in activity like swimming. Hence, the compounds of the present invention are designed to address the need for highly water-soluble yet substantially substantive sunscreen molecules.
Thus the present invention provides novel, substantive, water-soluble bis-cinnamidoalkylamine quaternary compounds of Formula I, 
wherein R1 represents up to four substituents, same or different, selected from H, halo, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94N(CH3)2, alkyl groups containing up to 6 carbon atoms, alkoxy groups containing up to 6 carbon atoms, alkylamino or N,N-dialkylamino groups containing up to 6 carbon atoms;
R2 is selected from hydrogen, alkyl group containing up to 6 carbon atoms;
R3 and R4 are independently selected from benzyl, alkyl group containing up to 6 carbon atoms;
n is an integer from 1 to 6; rn is an integer from 1 to 10;
Xxe2x88x92 is a counter anion of quaternary centres selected from halides including chloride, bromide, iodide and methane sulphonate and its derivatives such as trifluoro methane sulphonate, benzene sulphonates including its p-bromo, nitro and methyl derivatives.
The invention further relates to a process of making a water-soluble quaternary ammonium salt of bis-cinnamidoalkylamine of Formula I 
wherein R1 represents up to four substituents, same or different, selected from H, halo, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94N(CH3)2, alkyl groups containing up to 6 carbon atoms, alkoxy groups containing up to 6 carbon atoms, alkylamino or N,N-dialkylamino groups containing up to 6 carbon atoms;
R2 is selected from hydrogen, alkyl group containing up to 6 carbon atoms;
R3 and R4 are independently selected from benzyl, alkyl group containing up to 6 carbon atoms;
n is an integer from 1 to 6; m is an integer from 1 to 10;
xe2x80x94Xxe2x88x92 is a counter anion of quaternary centres selected from halides including chloride, bromide, iodide and methane sulphonate and its derivatives such as trifluoro methane sulphonate, benzene sulphonates including its p-bromo, nitro and methyl derivative;
wherein, a compound of Formula II is first reacted with a compound of Formula III and the intermediate of Formula IV thus obtained is quatemised with a compound of Formula V, 
wherein in all these Formulae, R1, R2, R3, R4, m, n and Xxe2x88x92 have the same meaning as Formula I and R5 of Formula II is selected form xe2x80x94OH, Clxe2x88x92 or xe2x80x94O(CH2)pCH3 with p=0 to 3.
In another aspect this invention provides compositions containing quaternary ammonium compounds that are water-soluble, UV-absorbing and substantive to skin, hair and textile fibres. The unique combination of substantivity to hair and skin, strong UV absorption and water-solubility of these quaternary compounds of bis-cinnamidoalkylamines is very desirable for personal care products, especially for skin care applications.
The UV absorbing compounds of the present invention are quaternary salts of cinnamidoalkylamines that are prepared by reacting lower alkyl ester of cinnamic acid or acid halides of cinnamic acid with an amino compound that is subsequently quaternised with bifunctional alkylating agents.
In the process, the amidification reaction between a compound of the Formula II when R5=xe2x80x94OH or xe2x80x94O(CH2)pCH3 (p=0 to 3), with that of Formula Ill is carried out at from about 120xc2x0 C. to about 200xc2x0 C., under pressure from about 10 psi to about 100 psi, in the presence of a basic catalyst such as sodium methoxide, sodium hydroxide from 0.25% to 5.0% by weight of the reaction mass, to afford the intermediate compound of Formula IV. 
Preferred amount of such catalyst is 1.0% w/w of total reaction mass. The reaction is conveniently monitored by TLC or HPLC using UV detection. After the complete disappearance of cinnamic acid ester, the excess diamine is distilled off under vacuum.
Alternately, this reaction is carried out in the presence of a basic catalyst such as sodium methoxide, sodium hydroxide from 0.25% to 5.0% by weight of the reaction mass under atmospheric pressure, under blanket of nitrogen, with an arrangement for continuous selective removal of lower alcohol formed in the reaction.
Thus, the condensation reaction of one mole of cinnamic acid ester is carried with 1.0 to 3.0 moles of diamine at 120 to 200xc2x0 C., preferably at 180xc2x0 C., for 12 to 36 hours. The amines themselves can catalyse the reaction, however, the rates are found to be slower as compared with the bases like sodium methoxide and the like.
The same reaction can be performed using cinnamic acid in place of cinnamic acid ester at temperatures up to 200xc2x0 C. and pressures of 100 psi, keeping the same stoichiometry (1:1.0 to 3). The excess diamine serves as solvent for the reaction.
Cinnamic acid esters and amino compounds are selected that are liquid within the disclosed temperature and pressure range.
The amidification reaction between a compound of Formula II when R5=xe2x80x94Cl in the presence of a solvent, is carried out with that of Formula III at room temperature in the presence of solvent. The compounds of Formula IV are synthesised by reacting acid chlorides of Formula II (1.0 mole) when R5 is xe2x80x94Cl with the diamines of Formula III (1.0 to 1.2 mole) at 20-50xc2x0 C. in an inert solvent like dichloromethane, ethylene dichloride, tetrahydrofuran and the like.
In the process the cinnamidoalkylamines (Formula IV, I mole) are N-alkylated with bifunctional quaternising agents (Formula V, 0.5 mole, wherein, Xxe2x88x92 is same as in Formula I) in the presence of a suitable inert solvent that governs the temperature at which the reaction is carried out. 
Quaternization of cinnamidoamines is carried out in the inert solvents that include lower alkanols, glycols, water and combinations thereof. Lower alkanols having one to four carbons atoms are suitable for use with the present invention. Glycols having from three to eight carbon atoms are suitable for use with the present invention. However, water is the most suitable solvent. The inert solvents are present in the reaction mass to extent of 20 to 80% resulting in solids content of final product from 80 to 20%.
The quaternisation reaction can be conveniently done in a pressure reactor as well as in an open system. The temperatures suitable for pressure reaction range from about 60-120xc2x0 C. with the pressures up to 50 psi. The pressures are governed by the amount of solvent and the temperature selected for the reaction. The conditions of reaction in an open vessel also get dictated by the choice of solvent. The reactions are usually carried out at boiling point or slightly below boiling point of the solvent employed. The resulting bis-quaternary salts are obtained as concentrated solutions in either water, or an inert solvent. The progress of the reaction is monitored by measuring the amount of unreacted alkylating agent by chromatography or by estimation of unquaternized amidoamine or by estimation of Xxe2x88x92.
On quaternizatteon, the alcoholic solvents or water can be easily removed from concentrated solutions of quaternary ammonium salts to obtain solvent free pure compounds. However, they are slightly tacky, hygroscopic solids and difficult to handle. Hence, it is convenient to market or use these products as concentrated solutions.
Since most of the quaternizations are conveniently carried out in aqueous medium, the bis-quaternaries of the present invention may be marketed in this form for many end-use applications such as hair care, skin care and fabric care compositions.
The UV-absorbing compounds of the present invention are bis-quaternary salts of cinnamic acid amido amines. The cinnamic acid amido amines are prepared by reacting lower alkyl esters of cinnamic acid with an amino compound having a second tertiary amino group that is subsequently quaternized. Thus, the precursors of the present invention include essentially any quaternizable reaction product of lower alkyl ester of cinnamic acid and amino compound having a second tertiary amino group, provided that both the reactants are not very hydrophobic so that on quaternizing, the quaternary compounds formed are not rendered water-insoluble.
The compounds of the present invention include bis-quaternary amidoamine linked through oxyethylene bridge between the two quaternary centres. The object of this invention is to obtain UV absorption through cinnamido moiety, significant levels of substantivity through two cationic centres and finally excellent water solubility from the cationic centres as well as oxyethylene chain between the two quaternary centres.
The number and their nature of selected substituents should not be too hydrophobic to render the final bis-quaternary water-insoluble. For purposes of the present application, water-soluble compounds are defined as being soluble in water at levels above 15% w/w. These water-soluble compounds of this invention are useful for making compositions for skin and hair care and fabric care.
The preferred bis-quaternary compounds in accordance with the present invention form aqueous solutions at levels of at least about 15% by weight. The more preferred quaternary compounds in accordance with the present invention have a solubility of at least about 25% by weight. The most preferred compounds have a water-solubility of at least 50% w/w.
The bis-quaternary ammonium compounds in accordance with the present invention have the structure of Formula I.
As shown in Formula I, the benzene ring preferably contains one substituent at para position, R1 is selected from moieties such as halo, p-OH, xe2x80x94NH2, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94N(CH3)2.
Referring again to Formula I, the amido nitrogen is preferably is either unsubstituted (R2 is hydrogen) or may contain a substituent, selected from alkyl groups containing up to 6 carbon atoms.
The quaternized nitrogen of the compounds in accordance with the present invention preferably contains two substituents, R3 and R4, as depicted in Formula I, R3 and R4 are independently selected from hydrogen, benzyl and alkyl groups containing up to 6 carbon atoms.
The compounds of the present invention are bis-quaternary salts of cinnamidoalkylamines as shown in Formula I, in which n is an integer between 1 and 6, both inclusive. Preferred compounds in accordance with the present invention are bis-quaternary salts of cinnamidoalkylamines in which n is an integer between 2 and 6, both inclusive and most preferably, n of Formula I is 3.
The compounds of the present invention are bis-quaternary salts of cinnamidoalkylamines as shown in Formula I, in which m is an integer between 1 to 10, both inclusive. The preferred value for m is between 2 to 6.
The bis-quaternary salts of the present invention are formed from bifunctional alkylating agent and its homologues where m is an integer between 2 and 6, both inclusive (Formula V). It is well understood by those with ordinary skill in the art, that the bis-quaternary salts of the present invention, will also include an anion derived from quaternisation reactions. Given the quaternizing agents described above, the quaternary salts of the present invention will contain an anion, such as Xxe2x88x92 of Formula I, selected from chloride, bromide, iodide, sulphate, alkosulphate, mesylate, triflate, tosylate and the like.
In another embodiment the process of the present invention relates to manufacture of a compound of Formula I, namely, xcex2, xcex2xe2x80x2-di(p-methoxy cinnamidopropyldimethyl ammonium chloride)ethyl ether, when R1=xe2x80x94OCH3, R2=H, R3=R4=xe2x80x94CH3, Xxe2x88x92=Clxe2x88x92, m=1 and n=3, from the compounds of Formula II, namely, p-methoxy ethyl cinnamate), and Formula III, namely, N,N-dimethylpropyldiamine, to form an intermediate compound of Formula IV, namely, p-methoxy cinnamidopropyldimethyl amine and Formula V, namely, bis-2-chloroethyl ether, with respective substituents R1 of Formula II, R2, R3, R4 and n of Formula III and Xxe2x88x92 and m of Formula V as defined for the compounds of Formula I in this embodiment, and R5 of Formula II being ethoxy.
Cinnamidoalkylamine (Formula IV) are in turn synthesized by amidification of lower alkyl esters of cinnamic acid (Formula II, alkoxy group (R5) may vary from C1 to C4) by appropriate diamines (Formula III) containing a tertiary amino group. R1, R2, R3 and R4 of cinnamidoalkylamine (Formula IV) and the diamine (Formula III) are the same as described with respect to Formula I.
The amidification reaction is performed at temperatures up to 200xc2x0 C. and pressures up to 100 psi. Accordingly, cinnamic acid esters and amino compounds are selected that are liquid within the disclosed temperature and pressure range. This reaction generates lower alcohol that need not be distilled out.
In the present invention the reaction of one mole of cinnamic acid ester is carried with 1.2 to 3 moles of diamine at 130 to 200xc2x0 C., preferably at 180xc2x0 C., for 12 to 36 hours. This condensation is catalysed by bases such as sodium hydroxide, sodium methoxide or ethoxide, potassium hydroxide and the like. The amines themselves can catalyse the reaction, however, the rates are found to be slower as compared with the bases like sodium methoxide and the like.
From about 0.5% to 5.0% w/w of the basic catalyst should be employed. Preferred amount of such catalyst is 1.0% w/w. The reaction is conveniently monitored by TLC or HPLC using UV detection. After the complete disappearance of cinnamic acid ester the excess diamine is distilled off under vacuum.
This amidification can also be carried out under atmospheric pressure under blanket of nitrogen with an arrangement for selective condensation of the diamine and continuous removal of lower alcohol. The same reaction can be performed using cinnamic acid in place of cinnamic acid ester at temperatures up to 200xc2x0 C. and pressures of 100 psi, keeping the same stoichiometry (1:1.2 to 3). The excess diamine serves as solvent for the reaction.
The bis-quaternaries (Formula I) of the present invention are synthesized as concentrated solutions by N-alkylating cinnamidoamines (Formula IV) with bifunctional alkylating agents having Formula V.
In another aspect this invention provides compositions containing quaternary ammonium compounds that are water-soluble, UV-absorbing and substantive to skin, hair and textile fibres. The hair care and skin care compositions containing compounds of Formula I can be solutions, dispersions or emulsions. The quaternary compounds of Formula I are soluble in water, alcohols, glycols, mixtures thereof, mixtures of alcohols and water and mixtures of glycols and water.
Lotions may be formed using compounds of Formula I, with or without one or more of the inert solvents like ethyl alcohol, isopropyl alcohol or propylene glycol, by combining with film forming polymers like proteins, polyvinyl pyrrolidone, polyvinyl alcohols and the like, film-forming starches and resins and the like.
Oil-in-water and water-in-oil emulsion can also be employed as vehicles to form lotions and creams. Conventional oil soluble UV-absorbing compounds like cinnamates, salicylates, p-aminobenzoates, benzophenones can be dissolved in oily phase of emulsion/lotions. The water-soluble sunscreens of the present invention are dissolved in an aqueous phase of the emulsion and combined with the oily phase using a suitable cationic emulsifier such as stearylkonium chloride.
Vegetable or mineral oils suitable for use as oil phase include mineral oil, petroleum, castor oil, sesame oil and the like. The quaternary ammonium compounds of the present invention are added to aqueous phase which is then subsequently emulsified with oily phase using an emulsifier like stearylkonium chloride or non-ionic emulsifiers like polysorbate-80, fatty alcohol ethoxylates and the like.
Perfumes, fragrances, anti-oxidants, preservatives, dyes colorants, insect repellents, fillers and suspended particulate matter, emollients, humectants, thickeners and the like may optionally be included in the sunscreen and tanning compositions of the present invention.
The sunscreen and tanning compositions of the present invention contain an effective amount of compounds of Formula I to prevent erythema. In general, an amount of about 0.5% to 10% w/w of the total composition is used.
Face powder compositions of the present invention contain compounds of Formula I in an effective amount of 0.1% w/w to 0.5% w/w.
The compositions containing compounds of Formula I may contain one or more of the other ingredients selected form cosmetic agents such as surfactants, other sunscreen chemicals, after sun treatment materials, emollients, humectants, perfumes, anti-perspirants, moisturisers, color cosmetic materials, herbal extracts, occlusive oils and essential oils.
The compositions of compound with Formula I provide hair protection from UV radiation in addition to good conditioning effect. The hair protecting preparations can be formulated in the form of creams, lotions, tonics or gels.
The compounds of the present invention may also be formulated as hair care product such as shampoos, cream rinses, hair conditioners, hair dressing preparations, hair relaxers, hair coloring products and the like, capable of protecting hair from UV-B radiation.
The rinse-off preparations like shampoos, face washes and bathing bars contain 0.5 to 8.0% w/w of compounds of Formula I. It may be noted that these quaternaries are compatible with usual anti-dandruff, anti-microbial agents like Zinc pyrithione, Irgasan, Pyroctone. Hence, these compounds of Formula I can be incorporated in anti-dandruff shampoos.
Despite their cationic nature, the compounds of Formula I are completely compatible with anionic surfactants like sodium lauryl ether sulphate. The water insolubility and cationic nature does not affect transparency of transparent shampoo. The shampoo formulation thus made has been shown to deposit the quaternary compounds on hair (Example III). The cream hair conditioner is an example of emulsion type with both water-soluble and water-insoluble sunscreens is given in Example IV.
Soap bars, both opaque and transparent I translucent can be formulated with compounds of UV-absorbing compounds of Formula I. In soap bars, the cinnamidoalkyl quaternary ammonium compounds can be incorporated from 0.5 to 10.0% w/w, more preferably from 1.0 to 2.0% w/w of total composition. It may be noted that the compounds of Formula I in the following combi-bar formulation are compatible with anionic surfactants (Example V).
For everyday use a sunscreen cream to protect the skin from both UV-A and UV-B radiation can be formulated as given in Example VI. The substantive UV absorbers, both water-insoluble and water-soluble (compounds of Formula I) can be conveniently incorporated at 2.0% each w/w of total composition. To cover UV-A range butyl methoxy dibenzoyl methane (Parsol 1789) is incorporated.
Furthermore, the compounds of Formula I of the present invention can be effectively incorporated into typical detergent powder and household cleaning product compositions to impart anti-fading effect to colored fabric through substantivity. Typical detergent and household cleaning product compositions in accordance with the present invention include one or more surfactants, selected from anionic, cationic, nonionic and amphoteric detergents, alone or in combination. A typical detergent powder has been shown to deposit cationic photofilters of the present invention on fabric (Example VII).
The hair and skin protecting and detergent and household cleaning compositions of the present invention are also formed by admixing, dissolving the compounds of Formula I into the desired cosmetically acceptable diluent and carrier. The preferred cosmetic compositions are solutions, dispersions or emulsions. The compositions contain an effective amount of one or more of UV-absorbing and conditioning compounds of the present invention to prevent erythema and darkening of skin due to solar damage.
In general, an amount of about 0.5% to about 10% w/w and preferably between 2.5 to 8.0% w/w of total cosmetic composition of compounds of Formula I are useful in personal hair and skin care products, sunscreens and tanning lotions. Typically, the ingredients are combined with mixing and heating if necessary until a uniform, homogeneous product is formed. With respect to the emulsion products of the present invention, the water-soluble and water-insoluble ingredients are mixed together separately and combined with suitable emulsifier, preferably a cationic emulsifier, to form an emulsion.
Finally, the substantive UV-B absorbers of the present invention are non-hydrolysable and contain the most widely used chromophore of cinnamido moiety for UV absorption. A representative substantive bis-quaternary compound of the present invention, xcex2,xcex2xe2x80x2-di (p-methoxy cinnamidopropyldimethylammonium chloride) ethyl ether, has molar extinction coefficient, xcex5 of 42,000. It is non-irritant and non-mutagenic. High water-solubility coupled with substantivity of the compounds of the present invention, is very much desired in cosmetic formulations without an oily phase. Unlike the quaternary UV-absorbers of previous art that are described as water-dispersible/soluble, the bis-quaternary compounds of the present invention exhibit high water-solubility due to oxyethylene bridge between two UV-absorbing moieties.